Vytautas Usonis

Rotavirus genotypes co-circulating in Europe between 2006 and 2009 as determined by EuroRotaNet, a pan-European collaborative strain surveillance network

EuroRotaNet, a laboratory network, was established in order to determine the diversity of co-circulating rotavirus strains in Europe over three or more rotavirus seasons from 2006/2007 and currently includes 16 countries. This report highlights the tremendous diversity of rotavirus strains co-circulating in the European population during three years of surveillance since 2006/2007 and points to the possible origins of these strains including genetic reassortment and interspecies transmission. Furthermore, the ability of the network to identify strains circulating with an incidence of ≥1% allowed the identification of possible emerging strains such as G8 and G12 since the beginning of the study; analysis of recent data indicates their increased incidence. The introduction of universal rotavirus vaccination in at least two of the participating countries, and partial vaccine coverage in some others may provide data on diversity driven by vaccine introduction and possible strain replacement in Europe.

European Society for Paediatric Infectious Diseases/European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Evidence-Based Recommendations for Rotavirus Vaccination in Europe

Timo Vesikari, yPierre Van Damme, zCarlo Giaquinto, §Jim Gray, jjJacek Mrukowicz, Ron Dagan, #Alfredo Guarino, Hania Szajewska, and yyVytautas Usonis, Expert Working Group Vaccine Research Centre, University of Tampere Medical School, Tampere, Finland, {Centre for the Evaluation of Vaccination, Vaccine and Infectious Disease Institute, Faculty of Medicine, University of Antwerp, Antwerp, Belgium, {Department of Paediatrics, University of Padova, Padova, Italy, §Centre for Infections, Health Protection Agency, London, UK, jjPolish Institute for Evidence-Based Medicine, Krakow, Soroka University Medical Center and the Faculty of Health Sciences, Journal of Pediatric Gastroenterology and Nutrition 46:615–618 # 2008 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

Rotavirus Surveillance in Europe, 2005–2008: Web-Enabled Reporting and Real-Time Analysis of Genotyping and Epidemiological Data

BACKGROUND The first European rotavirus surveillance network, EuroRotaNet, comprising 16 laboratories in 15 European countries, has been established. METHODS Fecal samples from gastroenteritis cases positive for group A rotavirus antigen were collected from multiple European countries from 2005 to mid-2008 and were subjected to G and P genotyping. Epidemiological data collected included age, sex, geographical location, setting, dates of onset and sample collection, and clinical symptoms. RESULTS A total of 8879 rotavirus-positive samples were characterized: 2129 cases were from the 2005-2006 season, 4030 from the 2006-2007 season, and 2720 from the ongoing 2007-2008 season. A total of 30 different G and P type combinations of strains circulated in the region from 2005 through 2008. Of these strains, 90% had genotypes commonly associated with human infections-G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]-and 1.37% represented potential zoonotic introductions. G1P[8] remained the most prevalent genotype in Europe as a whole, but the incidence of infection with G1P[8] rotavirus strains was <50% overall, and all 3 seasons were characterized by a significant diversity of cocirculating strains. The peak incidence of rotavirus infection occurred from January through May, and 81% of case patients were aged <2.5 years. Conclusions. Data gathered through EuroRotaNet will provide valuable background information on the rotavirus strain diversity in Europe before the introduction of rotavirus vaccines, and the network will provide a robust method for surveillance during vaccine implementation.

Reactogenicity and immunogenicity of a new live attenuated combined measles, mumps and rubella vaccine in healthy children

OBJECTIVE To compare the reactogenicity and immunogenicity of a novel live attenuated measles-mumps-rubella vaccine, SB MMR (Priorix; SmithKline Beecham Biologicals), with a widely used MMR vaccine, Merck MMR (M-M-R II; Merck & Co. Inc). METHODS A total of 4702 healthy children, ages 9 to 24 months, were enrolled in 8 single blind, randomized, controlled trials. Reactogenicity (local and general solicited symptoms and all unsolicited symptoms) was assessed for up to 42 days postvaccination. Immunogenicity [seroconversion rates and geometric mean titers (GMT)] was assessed at 42 or 60 days postvaccination in 1912 subjects in 7 studies. In two studies the persistence of the antibodies at Month 12 postvaccination was assessed in 201 subjects. RESULTS Local symptoms (pain on or immediately after injection; pain, redness and swelling within 4 days of injection) were reported less frequently after SB MMR than Merck MMR (P < 0.0001). General symptoms and all other events were similar between the two groups. Fever >39.5 degrees C was reported after 9.5 and 11.9% of the SB MMR and Merck MMR doses, respectively. At Days 42 to 60 postvaccination seroconversion rates for antimeasles antibodies were higher with SB MMR than with Merck MMR (98.7% vs. 96.9%, P < 0.031) but similar in both groups for anti-mumps and anti-rubella antibodies, GMTs being approximately 10% higher (P < 0.05) with Merck MMR than with SB MMR. At the Month 12 assessment the seropositivity rates and GMTs were similar in both groups. CONCLUSION When administered as primary vaccination in children in the second year of life, the new SB MMR vaccine has been shown to be superior to a comparator vaccine in terms of local reactogenicity, with equivalent immunogenicity.

Antibody titres after primary and booster vaccination of infants and young children with a virosomal hepatitis A vaccine (Epaxal).

To evaluate the immunogenicity and tolerability of Epaxal in infants and children, 30 infants (aged 6-7 months) and 30 children (aged 5-7 years) received a single intramuscular dose of the aluminium-free virosomal hepatitis A virus (HAV) vaccine Epaxal and a booster dose after 12 months. Anti-HAV antibody titres were measured at baseline (before injection), at 1 and 12 months after primary vaccination, and 1 month after the booster vaccination. Sixteen evaluable infants had maternal anti-HAV antibodies at baseline. Complete seroprotection (titre >/= 20 mIU/ml) was achieved by all infants and children at Month 1 and at Month 12. Additionally, all subjects showed a strong antibody response to booster vaccination. In infants without maternal anti-HAV antibodies, the response was four-fold higher than in those with maternal anti-HAV antibodies. Both doses of Epaxal were well tolerated. These preliminary data suggest that Epaxal is an effective hepatitis A vaccine for children and infants from 6 months of age.

Antibiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat?

Community-acquired pneumonia (CAP) is a common cause of morbidity among children in developed countries and accounts for an incidence of 10-40 cases per 1000 children in the first 5 years of life. Given the clinical, social and economic importance of CAP, there is general agreement that prompt and adequate therapy is essential to reduce the impact of the disease. The aim of this discussion paper is to consider critically the available data concerning the treatment of uncomplicated pediatric CAP and to consider when, how and for how long it should be treated. This review has identified the various reasons that make it difficult to establish a rational approach to the treatment of pediatric CAP, including the definition of CAP, the absence of a pediatric CAP severity score, the difficulty of identifying the etiology, limited pharmacokinetic (PK)/pharmacodynamic (PD) studies, the high resistance of the most frequent respiratory pathogens to the most widely used anti-infectious agents and the lack of information concerning the changes in CAP epidemiology following the introduction of new vaccines against respiratory pathogens. More research is clearly required in various areas, such as the etiology of CAP and the reasons for its complications, the better definition of first- and second-line antibiotic therapies (including the doses and duration of parenteral and oral antibiotic treatment), the role of antiviral treatment and on how to follow-up patients with CAP. Finally, further efforts are needed to increase vaccination coverage against respiratory pathogens and to conduct prospective studies of their impact.Community-acquired pneumonia (CAP) is a common cause of morbidity among children in developed countries and accounts for an incidence of 10–40 cases per 1000 children in the first 5 years of life. Given the clinical, social and economic importance of CAP, there is general agreement that prompt and adequate therapy is essential to reduce the impact of the disease. The aim of this discussion paper is to consider critically the available data concerning the treatment of uncomplicated pediatric CAP and to consider when, how and for how long it should be treated. This review has identified the various reasons that make it difficult to establish a rational approach to the treatment of pediatric CAP, including the definition of CAP, the absence of a pediatric CAP severity score, the difficulty of identifying the etiology, limited pharmacokinetic (PK)/pharmacodynamic (PD) studies, the high resistance of the most frequent respiratory pathogens to the most widely used anti-infectious agents and the lack of information concerning the changes in CAP epidemiology following the introduction of new vaccines against respiratory pathogens. More research is clearly required in various areas, such as the etiology of CAP and the reasons for its complications, the better definition of first- and second-line antibiotic therapies (including the doses and duration of parenteral and oral antibiotic treatment), the role of antiviral treatment and on how to follow-up patients with CAP. Finally, further efforts are needed to increase vaccination coverage against respiratory pathogens and to conduct prospective studies of their impact.

Facilitating the WHO Expanded Program of Immunization: the clinical profile of a combined diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b vaccine

BACKGROUND Vaccines are important weapons in the fight against infectious diseases. The World Health Organization (WHO) Expanded Program on Immunization (EPI) has been extended to include recommendations for hepatitis B and Haemophilus influenzae type b (Hib) vaccinations. The WHO has recommended that combined vaccines be used where possible, to reduce the logistic costs of vaccine delivery. This paper reviews the efficacy, safety and cost-effectiveness of Tritanrix-HB/Hib, the only commercially available combined diphtheria, tetanus, whole cell pertussis, hepatitis B and conjugated Hib vaccine. METHODS The immunogenicity and reactogenicity results of five published clinical trials involving Tritanrix-HB/Hib in a variety of immunization schedules and countries were reviewed. Based on these data and cost-effectiveness studies, an assessment of its suitability for use in national immunization programs was made. RESULTS Tritanrix-HB/Hib has shown excellent immunogenicity in clinical trials using a variety of schedules, with no reduced immunogenicity observed for any of the components of the combined vaccine. It has similar reactogenicity to DTPw vaccines alone. Pharmacoeconomic analyses have shown combined DTP-HB/Hib vaccines to be cost-effective compared to separate vaccines. CONCLUSIONS Replacement of DTPw vaccination by Tritanrix-HB/Hib can be done without modifying the existing national immunization programs. This should facilitate widespread coverage of hepatitis B and Hib vaccinations and their rapid incorporation into the EPI.

Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial

BACKGROUND Rates of varicella have decreased substantially in countries implementing routine varicella vaccination. Immunisation is possible with monovalent varicella vaccine or a combined measles-mumps-rubella-varicella vaccine (MMRV). We assessed protection against varicella in naive children administered one dose of varicella vaccine or two doses of MMRV. METHODS This study was done in ten European countries with endemic varicella. Healthy children aged 12-22 months were randomised (3:3:1 ratio, by computer-generated randomisation list, with block size seven) to receive 42 days apart (1) two doses of MMRV (MMRV group), or (2) MMR at dose one and monovalent varicella vaccine at dose two (MMR+V group), or (3) two doses of MMR (MMR group; control). Participants and their parents or guardians, individuals involved in assessment of any outcome, and sponsor staff involved in review or analysis of data were masked to treatment assignment. The primary efficacy endpoint was occurrence of confirmed varicella (by detection of varicella zoster virus DNA or epidemiological link) from 42 days after the second vaccine dose to the end of the first phase of the trial. Cases were graded for severity. Efficacy analyses were per protocol. Safety analyses included all participants who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, number NCT00226499. FINDINGS Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. In the efficacy cohort of 5285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8·8), in the MMR+V group was 36 months (8·5) and in the MMR group was 35 months (8·9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94·9% (97·5% CI 92·4-96·6), and against moderate to severe varicella was 99·5% (97·5-99·9). Efficacy of one-dose varicella vaccine against all varicella was 65·4% (57·2-72·1), and against moderate to severe varicella (post hoc) was 90·7% (85·9-93·9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57·4% (95% CI 53·9-60·9) of participants in the MMRV group reported fever of 38°C or more, by contrast with 44·5% (41·0-48·1) with MMR+V, and 39·8% (33·8-46·1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period. INTERPRETATION These results support the implementation of two-dose varicella vaccination on a short course, to ensure optimum protection from all forms of varicella disease. FUNDING GlaxoSmithKline Vaccines.

Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for influenza vaccination in children

BackgroundInfluenza vaccination in infants and children with existing health complications is current practice in many countries, but healthy children are also susceptible to influenza, sometimes with complications. The under-recognised burden of disease in young children is greater than in elderly populations and the number of paediatric influenza cases reported does not reflect the actual frequency of influenza.DiscussionVaccination of healthy children is not widespread in Europe despite clear demonstration of the benefits of vaccination in reducing the large health and economic burden of influenza. Universal vaccination of infants and children also provides indirect protection in other high-risk groups in the community. This paper contains the Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for the vaccination of infants and children against influenza. The aim of CEVAG is to encourage the efficient and safe use of vaccines to prevent and control infectious diseases.SummaryCEVAG recommends the introduction of universal influenza vaccination for all children from the age of 6 months. Special attention is needed for children up to 60 months of age as they are at greatest risk. Individual countries should decide on how best to implement this recommendation based on their circumstances.

Comparative study of reactogenicity and immunogenicity of new and established measles, mumps and rubella vaccines in healthy children

SummaryConcerns about the association of aseptic meningitis with measles-mumpsrubella (MMR) vaccines containing the Urabe Am 9 strain and the increasing worldwide demand for MMR vaccines, prompted the development of a new mumps vaccine strain (RIT 4385) by SmithKline Beecham Biologicals (SB) as part of a trivalent live attenuated MMR vaccine. The present study assessed the immunogenicity and reactogenicity of two lots of ‘Priorix’* with a widely used and established vaccine M-M-R II (Merck & Co. Inc.) as comparator vaccine. 255 healthy children, 12 to 24 months of age, were enrolled in a single-blind study and randomly allocated to receive a single dose of one of two lots of “Priorix” or M-M-R II vaccine. Vaccinees were followed up for six weeks post-vaccination for solicited and unsolicited symptoms. Immunogenicity was determined in pre- and 60 days post-vaccination sera using commercial immunoassays for measles, mumps and rubella antibodies. There were no significant differences in immune responses between groups for any of the three vaccine components. In initially seronegative subjects, the respective post-vaccination seroconversion rates for ‘Priorix’ lots 1 and 2, and M-M-R II were 100, 100 and 97.6% for measles antibodies, 91.7, 95.1 and 94% for mumps antibodies and 100, 100 and 100% for rubella antibodies, respectively. GMTs for the three groups were 3,076, 3,641 and 3,173 mIU/ml for measles antibodies, 934, 900 and 1,043 U/ml for mumps antibodies, and 86.4, 87.5 and 97.1 IU/ml for rubella antibodies, respectively. The incidence of local symptoms was significantly lower for both ‘Priorix’ lots (17.6 and 15.3% for lots 1 and 2, respectively) than for M-M-R II (37.6%). Fever≧38.1°C during the six-week observation period occurred in approximately 25% of all subjects in all groups with no differences between the groups. No parotid/salivary gland swelling or signs of suspected meningism were reported, and there were no serious adverse events related to vaccination. The new MMR vaccine ‘Priorix’ containing the new RIT 4385 mumps strain was safe and had a significantly improved local tolerability profile over the comparator vaccine, M-M-R II, while eliciting an at least equivalent immune response.